MEF2C is one of four members of the MEF2 family of transcription factor. It is among the first genes expressed in cardiac development and is later expressed in all three muscle lineages, endothelial cells, neuronal cells, and many hematopoietic lineages. We have been investigating the function of MEF2C in cardiovascular development through analysis of mice deleted for this gene. We find that the MEF2C null mouse is defective in both cardiac and vascular morphogenesis. The most striking features of this mutant's heart are that the right ventricle is missing and the left ventricle is extremely hypoplastic. Additionally, the common atrium and sinus venosus are large relative to the rest of the heart. The mutant heart contracts in a peristaltic motion but there is no visible flow of blood outside of the heart. The vascular system of the mutant embryos is characterized by the contrasting phenotypes of extremely narrow, winding dorsal aortas in the region of the heart, but enlarged aortas caudal to the heart and a dilated head vasculature. The yolk sac vasculature forms a capillary network but never reorganizes into the normal branching pattern of variably sized vitelline vessels. Some aspects of these defects resemble vascular malformations observed in mice deleted for endothelial-specific receptors and growth factors. However, the defects are not similar enough to be attributable to the loss of a single signaling pathway. It is, therefore, our hypothesis that the entire constellation of defects results from alterations in endothelial- specific signally pathways and circulatory alterations caused by the abnormal heart. We propose to further characterize these defects and to critically test this hypothesis through a series of experiments. The first set of experiments will determine if the expressions of these receptors and growth factors are altered by immunohistochemistry and in situ hybridization. These experiments will also better define the nature of these defects through assays of apoptosis, proliferation, and vessel fusion. Another set of experiments will attempt to determine the relative contribution of the malformed heart to the vascular defects by rescuing the heart defects through specific expression of MEF2C in the hearts of MEF2C null mice. Lastly, the role in vascular formation of MEF2 in endothelial cells will be tested through specific expression of a repressing form of MEF2C in endothelial cells of normal mice.